This is a continuation of a research program that is supported by NIMH and NIDA for a number of years. The purpose of this research is to delineate some of the pharmacological and biochemical characteristics of tolerance and dependence to the narcotic analgesics. The investigations outlined will continue work on the characteristics and properties of tolerance and dependence and explore several avenues of approach to this problem. We propose to investigate factors involved in the appearance, maintenance and loss of tolerance and physical dependence as they relate to dose, dose intervals and the chemical structures of the narcotic analgesic administered. The study also proposes to continue the investigation of the interrelationship of tolerance and physical dependence with respect to onset, duration and disappearance. We plan to continue the investigation of the similarities between certain immunological reactions and tolerance. We shall carry out these studies using analgesic assays, measurements of temperature and locomotor activity as well as observations of various aspects of drug-seeking behavior. We will expand the exploration of the possibility of using one parameter of drug effect, namely temperature, as a measure of both tolerance and dependence. We will use the complex interrelationship of agonist and antagonist to further investigate the nature of the drug-receptor occupation and the nature of the initiation of the changes resulting in tolerance and dependence. Explorations of the prevention of tolerance and dependence by the concomitant administration to agonist and antagonist or by the prior administration of antagonist or by the subsequent administration of antagonist will be continued. Agents affecting protein synthesis and short-term memory will also be used to investigate the nature of this drug-receptor interaction more fully.